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At least 19 recordsLinked to original sources
PubMed2004

Molecular mechanisms through which amino acids mediate signaling through the mammalian target of rapamycin.

PURPOSE OF REVIEW: The purpose of this review is to provide a summary of the current state of knowledge concerning one of the intracellular signal transduction pathways through which amino acids, and in particular leucine, regulate the initiation phase of mRNA translation. The primary focus is on a protein kinase, termed the mammalian target of rapamycin (mTOR), that is a point of convergence between amino acid and growth factor signaling to mRNA translation and thereby to cell growth. RECENT FINDINGS: Until recently the pathway through which amino acids signal to mTOR was completely undefined. Several recent reports, however, describe the identification of proteins that modulate amino acid signaling through mTOR, that is the tuberous sclerosis complex proteins 1 and 2 and the Ras homolog enriched in brain (Rheb) protein. Tuberous sclerosis complex protein 2 is a GTPase activator protein for Rheb that is inhibited by amino acids, allowing Rheb to activate mTOR through a mechanism still to be delineated. In addition, two proteins that interact with mTOR to target it to two important substrates, eukaryotic initiation factor 4E binding protein 1 and ribosomal protein S6 kinase, have been identified. Both proteins, that is the regulatory associated protein of mTOR and G protein beta-subunit-like protein, are required for optimal signaling through mTOR by amino acids. SUMMARY: Studies reported in the past 18 months have greatly expanded our knowledge of one of the signaling pathways through which amino acids act to regulate mTOR and also the molecular interactions that mediate the interaction between mTOR and two downstream substrates, eukaryotic initiation factor 4E binding protein 1 and ribosomal protein S6 kinase.

Amino Acids↗
PubMed1995

Tumor suppressor genes as negative growth regulators in development and differentiation.

Tumor suppressor genes have received much attention for their roles in the development of human malignancies. However, their gene products (proteins) function as negative growth regulators and are highly expressed in many tissues during embryonic development, suggesting that they might function as critical proteins in differentiation and development. The evidence implicating tumor suppressor proteins in cellular differentiation and embryonic development will be presented with special attention to the neurofibromatosis 1, neurofibromatosis 2, and tuberous sclerosis 2 gene products.

Cell Cycle Proteins↗
PubMed2006

AKT-independent phosphorylation of TSC2 and activation of mTOR and ribosomal protein S6 kinase signaling by prostaglandin F2alpha.

Prostaglandin F2alpha (PGF2alpha) is an important mediator of corpus luteum (CL) regression, although the cellular signaling events that mediate this process have not been clearly identified. It is established that PGF2alpha binds to a G-proteincoupled receptor (GPCR) to stimulate protein kinase C (PKC) and Raf-MEK-Erk signaling in luteal cells. The present experiments were performed to determine whether PGF2alpha stimulates the mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase 1 (S6K1) signaling pathway in steroidogenic luteal cells. We demonstrate that PGF2alpha treatment results in a timeand concentration-dependent stimulation of the phosphorylation and activation of S6K1. The stimulation of S6K1 in response to PGF2alpha treatment was abolished by the mTOR inhibitor rapamycin. Treatment with PGF2alpha did not increase AKT phosphorylation but increased the phosphorylation of Erk and the tumor suppressor protein tuberous sclerosis complex 2 (TSC2), an upstream regulator of mTOR. The effects of PGF2alpha were mimicked by the PKC activator PMA and inhibited by U0126, a MEK1 inhibitor. The activation of mTOR/S6K1 and putative down stream processes involving the translational apparatus (i.e. 4EBP1 phosphorylation, release of 4EBP1 binding in m(7)G cap binding assays, and the phosphorylation and synthesis of S6) were completely sensitive to treatment with rapamycin, implicating mTOR in the actions of PGF2alpha. Taken together, our data suggest that GPCR activation in response to PGF2alpha stimulates the mTOR pathway which increases the translational machinery in luteal cells. The translation of proteins under the control of mTOR may have implications for luteal development and regression and offer new strategies for therapeutic intervention in PGF2alpha-target tissues.

Animals↗
PubMed1997

[VHL gene and TSC 2 gene].

Hereditary cancer is rare, but it has served as a useful model in the understanding of carcinogenesis. A number of cancer genes have been identified by the study of hereditary human cancers and implicated in sporadic forms of the some tumors. In this article, I reviewed von Hippel-Lindau disease (VHL) gene and tuberous sclerosis 2 (TSC 2) gene.

Animals↗
PubMed2004

Perturbed IFN-gamma-Jak-signal transducers and activators of transcription signaling in tuberous sclerosis mouse models: synergistic effects of rapamycin-IFN-gamma treatment.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by widespread development of hamartomas, which is caused by mutations in either TSC1 or TSC2. We demonstrate a dramatic decrease of IFN-gamma expression in tumors and mouse embryo fibroblast cell lines that lack either Tsc1 or Tsc2, which is reversed by rapamycin (mammalian target of rapamycin inhibitor) therapy. Increased signal transducers and activators of transcription (STAT) 1 expression and phosphorylation at Ser 727 and increased pSTAT3 Tyr705 levels also are seen in Tsc1 null and Tsc2 null cells and in tumors. Treatment of Tsc1 or Tsc2 null cells with IFN-gamma induces apoptosis, in contrast to control cell lines, with reduction in pSTAT3 Tyr705 levels and major increases in pSTAT1 Tyr701, bax, and caspase-1 and -9 levels. A combination of IFN-gamma and rapamycin is markedly synergistic in induction of apoptosis in Tsc1 or Tsc2 null cells because pSTAT3 Tyr705 phosphorylation is abolished completely and the other effects of IFN-gamma are maintained or enhanced. Rapamycin-IFN-gamma has unique potential therapeutic benefit for management of TSC tumors.

Animals↗
PubMed2004

Phosphorylation of tuberin as a novel mechanism for somatic inactivation of the tuberous sclerosis complex proteins in brain lesions.

Tuberous sclerosis complex is caused by mutations in tumor suppressor genes TSC1 or TSC2 and is characterized by the presence of hamartomas in many organs. Although tuberous sclerosis complex is a tumor suppressor gene syndrome with classic "second hits" detectable in renal tumors, conventional genetic analysis has not revealed somatic inactivation of the second allele in the majority of human brain lesions. We demonstrate a novel mechanism of post-translational inactivation of the TSC2 protein, tuberin, by physiologically inappropriate phosphorylation, which is specific to tuberous sclerosis complex-associated brain lesions. Additional analysis shows that tissue specificity is due to abnormal activation of the Akt and mitogen-activated protein kinase pathways in brain but not in renal tumors. These results have widespread implications for understanding the tissue specificity of tumor suppressor gene phenotypes.

Astrocytoma↗
PubMed2003

Rap1 activity is elevated in malignant astrocytomas independent of tuberous sclerosis complex-2 gene expression.

Increased small GTPase protein mitogenic signaling is common in tumors. We have previously demonstrated that sporadic astrocytomas exhibit high levels of activated Ras important for tumor growth. Individuals with tuberous sclerosis complex (TSC) develop astrocytoma-like tumors resulting from mutations in the TSC2 protein, tuberin, which is hypothesized to function as a Rap1 GTPase activating protein (GAP). Since we have previously reported that high-grade astrocytomas frequently exhibit loss of tuberin expression or increased Rap1 levels, we sought to determine whether there is a correlation between decreased tuberin Rap1-GAP function or Rap1 overexpression and tumor Rap1 activity. In this study, we compared levels of Rap1-GTP, Rap1 and tuberin levels in normal brain tissue and 24 grade II-IV astrocytoma specimens. Whereas Rap1 overexpression was observed in astrocytomas of all malignancy grades, tuberin loss was seen most frequently in the higher-grade astrocytomas. In the grade IV glioblastoma multiforme tumors, Rap1 activity was 2-3-fold higher than in lower grade or non-neoplastic brain. However, there was no correlation between tuberin expression or Rap1 overexpression and the levels of Rap1 activity in the tumors studied, suggesting that the increased Rap1 activation is not the direct result of reduced tuberin Rap1-GAP function or elevated Rap1 protein expression.

Astrocytoma↗
PubMed2002

Tuberin, the tuberous sclerosis complex 2 tumor suppressor gene product, regulates Rho activation, cell adhesion and migration.

Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome characterized by seizures, mental retardation, autism, and tumors of the brain, kidney, heart, retina, and skin. TSC is caused by mutations in either TSC1 or TSC2, both of which are tumor suppressor genes. Hamartin, the protein product of TSC1, was found to interact with the ezrin-radixin-moesin family of cytoskeletal proteins and to activate the small GTPase Rho. To determine whether tuberin, the TSC2 product, can also activate Rho, we stably expressed full-length human tuberin in two cell types: MDCK cells and ELT3 cells. ELT3 cells lack endogenous tuberin expression. We found that expression of human tuberin in both MDCK and ELT3 cells was associated with an increase in the amount of Rho-GTP, but not in Rac1-GTP or cdc42-GTP. Tuberin expression increased cell adhesion in both cell types, and decreased chemotactic cell migration in ELT3 cells. In MDCK cells, there was a decrease in the amount of total Focal Adhesion Kinase (FAK) and an increase in the fraction of phosphorylated FAK. These findings demonstrate for the first time that tuberin activates Rho and regulates cell adhesion and migration. Pathways involving Rho activation may have relevance to the clinical manifestations of TSC, including pulmonary lymphangioleiomyomatosis.

Animals↗
PubMed2005

Expression profile of tuberin and some potential tumorigenic factors in 60 patients with uterine leiomyomata.

Human uterine leiomyomata are the most common tumors in women of reproductive age. The pathogenesis of leiomyomata remains unknown. An animal model of Eker rats with deleted tuberous sclerosis complex gene 2 (tuberin) shows increased incidence of leiomyomata. The role of tuberin in human leiomyomata is unknown. In this study, we designed a tissue microarray with tissue cores of leiomyomata and the matched myometrium from 60 hysterectomy specimens. We examined the expression of tuberin and tuberous sclerosis complex gene 1 product hamartin, proteins of the insulin-signaling pathway, steroid receptors and some of their cofactors, and human mobility group gene A2 by immunohistochemistry. We found that nearly half of the cases displayed either reduction or loss of tuberin in leiomyomata compared with matched normal myometrium. No change of hamartin was noted. Furthermore, a significant reduction of glucocorticoid receptor was found in leiomyomata with reduced tuberin. The proteins insulin like growth factor 1, insulin-like growth factor receptor beta, AKT kinase, and phosphatidylinositol 3-kinase were upregulated. Nearly half of leiomyomata show upregulation of human mobility group gene A2, along with the steroid receptor cofactors. Our findings suggest that there are two broad groups of uterine leiomyomata. One group is associated with an alteration of tuberin and glucocorticoid receptor. The other group is associated with upregulation of human mobility group gene A2 and steroid receptor cofactors.

Adult↗
PubMed2005

The tuberous sclerosis genes, TSC1 and TSC2, trigger different gene expression responses.

Tuberous sclerosis (TSC) is an autosomal dominant tumor suppressor gene syndrome affecting about 1 in 6000 individuals. It is characterized by mental retardation and epilepsy. A variety of tumors characteristically occur in different organs of TSC patients. The genes, TSC1 on chromosome 9q34, encoding hamartin, and TSC2 on chromosome 16p13.3, encoding tuberin are responsible for TSC. Hamartin and tuberin form a complex providing a tentative explanation for the similar disease phenotype in TSC patients with mutations in either of these genes. Besides overlap in many features of patients with TSC1 and TSC2 mutations, data accumulated provide evidence for specific clinical differences. Here, we performed microarray analyses of the gene expression response to overexpressed TSC1 or TSC2 in HeLa cells. Out of 2400 analysed genes we found 115 genes to be up-regulated > or =2-fold upon ectopic TSC1 overexpression and 284 genes to be up-regulated > or =2-fold via TSC2. Only 34 of these genes were up-regulated by both, TSC1 and TSC2. Whereas only 7 genes were down-regulated > or =2-fold via TSC1, ectopic TSC2 triggered a > or =2-fold down-regulation of 113 genes. Only 3 of these genes were down-regulated by TSC1 and TSC2. This study provides new insights into the cellular roles of TSC proteins and promotes discussion on whether separable functions of these proteins might be associated with the clinical differences of TSC1- and TSC2-associated disease.

Down-Regulation↗
PubMed1997

On the surgical treatment of refractory epilepsy in tuberous sclerosis complex.

The role of surgery in the treatment of refractory epilepsy (RE) in tuberous sclerosis complex (TSC) is poorly defined. Four patients with RE and TSC were evaluated for epilepsy surgery from 1994 to 1996. Three of four patients developed infantile spasms within 5 months of birth. These progressed to frequent complex partial and generalized tonic/myoclonic seizures refractory to antiepileptic drug therapy. Neuroimaging revealed typical findings of TSC including calcified lesions consistent with hamartomas. Clinical and EEG evidence suggested an epileptic focus near a prominent lesion in each child. This was confirmed using magnetic source imaging in 1 case. All patients underwent inpatient continuous video-EEG monitoring followed by temporal lobectomy or focal cortical resection with intraoperative EEG. Age at operation ranged from 5 to 13 years. Three out of 4 patients experienced a greater than 90% decrease in seizure activity. One patient continues to have rare complex partial seizures, and 1 has rare simple partial seizures. Tumor DNA analysis revealed mutations in the TSC1 gene in case 1 and the TSC2 gene in case 2; no mutations have been identified yet in cases 3 and 4. Temporal lobectomy and focal cortical resection can result in improved seizure control in patients with TSC and RE.

Adolescent↗
PubMed2005

Interferon-gamma-Jak-Stat signaling in pulmonary lymphangioleiomyomatosis and renal angiomyolipoma: a potential therapeutic target.

Pulmonary lymphangioleiomyomatosis (LAM) and renal angiomyolipoma (AML) are proliferative lesions that occur in sporadic patients, and at much higher frequency in patients with tuberous sclerosis (TSC). The TSC1 and TSC2 genes play a critical role in their pathogenesis. Here we report a marked decrease in interferon (IFN)-gamma expression in both sporadic and TSC-associated AML and LAM. A marked increase in Stat1 expression and phosphorylation at Ser 727, and in phospho-Tyr705-Stat3 levels, was also seen in both AML and LAM tissues. Our results demonstrate that the IFN-gamma-Jak-Stat pathway is perturbed in TSC-related and sporadic LAM and AML, and suggest that IFN-gamma has potential therapeutic benefit for treatment of those lesions.

Angiomyolipoma↗
PubMed2001

Tuberin phosphorylation regulates its interaction with hamartin. Two proteins involved in tuberous sclerosis.

Hamartin and tuberin are products of the tumor suppressor genes, TSC1 and TSC2, respectively. When mutated, a characteristic spectrum of tumor-like growths develop resulting in the syndrome of tuberous sclerosis complex. The phenotypes associated with TSC1 and TSC2 mutations are largely indistinguishable suggesting a common biochemical pathway. Indeed, hamartin and tuberin have been shown to interact stably in vitro and in vivo. Factors that regulate their interaction are likely critical to the understanding of disease pathogenesis. In this study, we showed that tuberin is phosphorylated at serine and tyrosine residues in response to serum and other factors, and it undergoes serial phosphorylation that can be detected by differences in electrophoretic mobilities. A disease-related TSC2 mutation (Y1571H) nearly abolished tuberin phosphorylation when stimulated with pervanadate. Expression of this mutant tuberin caused a marked reduction in TSC1-TSC2 interaction compared with wild-type protein and significantly curtailed the growth inhibitory effects of tuberin when overexpressed in COS1 cells, consistent with a loss of function mutation. Examination of a second pathologic mutation, P1675L, revealed a similar relationship between limited phosphorylation and reduced interaction with hamartin. Our data show for the first time that 1) tuberin is phosphorylated at tyrosine and serine residues, 2) TSC1-TSC2 interaction is regulated by tuberin phosphorylation, and 3) defective phosphorylation of tuberin is associated with loss of its tumor suppressor activity. These findings suggest that phosphorylation may be a key regulatory mechanism controlling TSC1-TSC2 function.

3T3 Cells↗
PubMed2006

Novel mutation in the TSC2 gene associated with prenatally diagnosed cardiac rhabdomyomas and cerebral tuberous sclerosis.

Cardiac rhabdomyomas are prenatal echocardiographic markers for tuberous sclerosis complex (TSC). TSC is caused by mutations in the genes TSC1 and TSC2. We report a 28-year-old, gravida 5, para 2, woman with an uncomplicated pregnancy until prenatal ultrasound at 34 weeks' gestation revealed fetal cardiac tumors. Ultrafast magnetic resonance imaging (MRI) at 36 weeks' gestation showed cardiac rhabdomyomas and small subependymal tubers. At 39 weeks' gestation, a 2,262 g female infant was delivered uneventfully. Postnatal echocardiography confirmed cardiac rhabdomyomas and MRI verified small cerebral subependymal tubers. Mutational analysis of TSC1 and TSC2 genes using denaturing high-performance liquid chromatography and direct sequencing of the genes was performed and revealed that the parents had wildtype DNA, while the proband was heterozygous for a novel de novo nonsense mutation, c.4830G >A, in exon 36 of the TSC2 gene, resulting in a change of codon 1610 TGG (tryptophan) to TGA (stop codon). The mutation predicted a W1610X premature termination of the tuberin protein. These findings support an association between a TSC2 de novo nonsense mutation and prenatally detected cardiac rhabdomyomas and cerebral tuberous sclerosis. Familial molecular analysis of TSC1 and TSC2 in cases with prenatally diagnosed cardiac rhabdomyomas and cerebral tuberous sclerosis lesions is helpful in prenatal diagnosis and genetic counseling.

Adult↗
PubMed2003

Down-regulation of cyclooxygenase-2 expression but up-regulation of cyclooxygenase-1 in renal carcinomas of the Eker (TSC2 gene mutant) rat model.

Although it is generally accepted that cyclooxygenase (Cox)-2 is overexpressed in carcinomas, few studies have examined Cox-2 expression in renal carcinoma (RC). The Eker rat RC is an example of a Mendelian dominantly inherited carcinoma, and in the present study, expression of Cox-2 in the Eker rat RC was examined. Reverse transcription polymerase chain reaction indicated constitutive expression of Cox-2 mRNA in the normal control kidney and non-tumor part of Eker rat kidney. Unexpectedly, expression of Cox-2 mRNA was down-regulated in four Eker RCs from two Eker rats, and in the cell line Lk9ds. Immunohistochemical analysis failed to reveal Cox-2 protein staining in Eker RCs. As a control to Cox-2 expression, Cox-1 expression was examined. Interestingly, in contrast to the down-regulated Cox-2 expression, Cox-1 mRNA expression was induced in these four Eker RCs and cell lines. Cox-2 and Cox-1 expression were further examined in six additional Eker RCs. In total, Cox-2 mRNA expression was down-regulated in eight out of ten Eker RCs and cell lines, while Cox-1 mRNA expression was up-regulated in nine out of ten Eker RCs and cell lines.

Animals↗
PubMed1999

Mutational analysis of TSC1 and TSC2 genes in Japanese patients with tuberous sclerosis complex.

We have surveyed the mutations of TSC1 and TSC2 from 38 (25 sporadic, 11 familial, and 2 unknown) Japanese patients with tuberous sclerosis complex. In 23 of 38 subjects, we detected 18 new mutations in addition to 4 mutations that had been previously reported. We also found 3 new polymorphisms. The mutations were not clustered on a particular exon in either of the genes. Seven TSC1 mutations found in 3 familial and 4 sporadic cases were on the exons (3 missense, 2 nonsense point mutations, a 1-base insertion, and a 2-bp deletion). Fifteen TSC2 mutations were found in 5 familial cases, 10 sporadic cases, and 1 unknown case. The 12 mutations were on the exons (8 missense, 1 nonsense point mutations, a 1-bp insertion, a 5-bp deletion, and a 4-bp replacement) and 3 point mutations were on the exon-intron junctions. Although the patients with TSC2 mutations tend to exhibit relatively severe mental retardation in comparison to those with TSC1 mutations, a genotype-phenotype correlation could not yet be established. The widespread distribution of TSC1/TSC2 mutations hinders the development of a simple diagnostic test, and the identification of individual mutations does not provide the prediction of prognosis.

Adolescent↗